Benzimidazole derivatives useful trpm8 channel modulators

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 0 , R 1 , R 2 , R 3 , R 4  and a are defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/185,681, filed on Jun. 10, 2009, which is incorporated by referenceherein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

FIELD OF THE INVENTION

The present invention is directed to benzimidazole derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders and conditions modulated by the TRPM8 (transientreceptor potential melastatin subfamily type 8) channel. The presentinvention also relates to processes for the preparation of benzimidazolederivatives and to their use in treating various diseases, syndromes,and disorders, including, those that cause inflammatory pain,neuropathic pain, cardiovascular diseases aggravated by cold, pulmonarydiseases aggravated by cold, and combinations thereof.

BACKGROUND OF THE INVENTION

Transient receptor potential (TRP) channels are non-selective cationchannels that are activated by a variety of stimuli. Numerous members ofthe ion channel family have been identified to date, including thecold-menthol receptor, also called TRPM8 (McKemy D. D., et al., Nature2002, 416(6876), 52-58). Collectively, the TRP channels and relatedTRP-like receptors connote sensory responsivity to the entire continuumof thermal stimulation, selectively responding to threshold temperaturesranging from noxious hot through noxious cold as well as to certainchemicals that mimic these sensations. Specifically, TRPM8 is known tobe stimulated by cool to cold temperatures as well as by chemical agentssuch as menthol and icilin, which may be responsible for the therapeuticcooling sensation that these agents provoke.

TRPM8 is located on primary nociceptive neurons (A-δ and C-fibers) andis also modulated by inflammation-mediated second messenger signals(Abe, J., et al., Neurosci Lett 2006, 397(1-2), 140-144; Premkumar, L.S., et al., J. Neurosci, 2005, 25(49), 11322-11329). The localization ofTRPM8 on both A-δ and C-fibers may provide a basis for abnormal coldsensitivity in pathologic conditions wherein these neurons are altered,resulting in pain, often of a burning nature (Kobayashi, K., et al., JComp Neurol, 2005, 493(4), 596-606; Roza, C., et al., Pain, 2006,120(1-2), 24-35; and Xing, H., et al., J Neurophysiol, 2006, 95(2),1221-30). Cold intolerance and paradoxical burning sensations induced bychemical or thermal cooling closely parallel symptoms seen in a widerange of clinical disorders and thus provide a strong rationale for thedevelopment of TRPM8 modulators as novel antihyperalgesic orantiallodynic agents. TRPM8 is also known to be expressed in brain,lung, bladder, gastrointestinal tract, blood vessels, prostate andimmune cells, thereby providing the possibility for therapeuticmodulation in a wide range of maladies.

There is a need in the art for TRPM8 antagonists that can be used totreat a disease, syndrome, or condition in a mammal in which thedisease, syndrome, or condition is affected by the modulation of TRPM8channels, such as pain, the diseases that lead to such pain, andpulmonary or vascular dysfunction.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

a is an integer from 0 to 3;

each R0 is independently selected from the group consisting of halogen,hydroxy, cyano, lower alkyl, fluorinated lower alkyl, lower alkoxy andfluorinated lower alkoxy;

R² is selected from the group consisting of hydrogen, halogen, hydroxy,cyano, lower alkyl, fluorinated lower alkyl, lower alkoxy andfluorinated lower alkoxy;

R¹ is selected from the group consisting of alkyl, hydroxy substitutedlower alkyl, halogenated lower alkyl, cycloalkyl-(lower alkyl)- andphenyl-(lower alkyl)-;

alternatively R² and R¹ are taken together as

(i.e. as —O—CH₂—CH₂—) or

(i.e. as —CH₂—CH₂—CH₂—);

R³ is selected from the group consisting of lower alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-(lower alkyl)-,aryl-(lower alkyl)-, heteroaryl-(lower alkyl)- andheterocycloalkyl-(lower alkyl)-;

wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group, is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, lower alkyl, halogenated lower alkyl, loweralkoxy, halogenated lower alkoxy, —C(O)OH, —C(O)O-(lower alkyl) and—C(O)—NR^(A)R^(B);

wherein R^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and lower alkyl; alternatively R^(A) and R^(B)are taken together with the nitrogen atom to which they are bound toform a 5 to 6 membered, saturated nitrogen containing ring structure;

R⁴ is selected from the group consisting of lower alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-(lower alkyl)-,aryl-(lower alkyl)-, heteroaryl-(lower alkyl)- andheterocycloalkyl-(lower alkyl)-;

wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group, is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, lower alkyl, halogenated lower alkyl, loweralkoxy, halogenated lower alkoxy and —S—CF₃;

provided that when R⁴ is heteroaryl or heterocycloalkyl, then the R⁴group is bound to the N of the compound of formula (I) through a carbonatom;

provided that when a is 0, R¹ is methyl, R² is hydrogen and R⁴ ismethyl; then R³ is other than methyl, phenyl or 4-methylphenyl;

and solvates, hydrates and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for thepreparation of the compounds of formula (I). The present invention isfurther directed to a product prepared according to the processdescribed herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the product prepared accordingto the process described herein. An illustration of the invention is apharmaceutical composition made by mixing the product prepared accordingto the process described herein and a pharmaceutically acceptablecarrier. Illustrating the invention is a process for making apharmaceutical composition comprising mixing the product preparedaccording to the process described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods of treating a disorder modulatedby TRPM8 (selected from the group consisting of inflammatory pain(including visceral pain), neuropathic pain (including neuropathic coldallodynia), cardiovascular disease aggravated by cold and pulmonarydisease aggravated by cold, in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament wherein themedicament is prepared for treating: (a) inflammatory pain, (b)neuropathic pain, (c) cardiovascular disease aggravated by cold, or (d)pulmonary disease aggravated by cold, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for the preparation ofcompound of formula (I)

wherein a, R⁰, R¹, R², R³ and R⁴ are as herein defined, andpharmaceutically acceptable salts thereof. The compounds of the presentinvention are useful in the treatment of disorders mediated by TRPM8,including inflammatory pain (including visceral pain), inflammatoryhyperalgesia, neuropathic pain (including neuropathic cold allodynia),inflammatory somatic hyperalgesia, inflammatory visceral hyperalgesia,cardiovascular disease aggravated by cold and pulmonary diseaseaggravated by cold.

In an embodiment of the present invention, a is an integer from 0 to 2.In another embodiment of the present invention, a is an integer from 0to 1. In another embodiment of the present invention, a is an integerform 1 to 2. In another embodiment of the present invention, a is 0.

In an embodiment of the present invention, each R⁰ is selected from thegroup consisting of halogen, lower alkyl, fluorinated lower alkyl, loweralkoxy and fluorinated lower alkoxy. In another embodiment of thepresent invention, each R⁰ is independently selected from the groupconsisting of halogen, C₁₋₂alkyl and fluorinated C₁₋₂alkyl. In anotherembodiment of the present invention, each R⁰ is independently selectedfrom the group consisting of fluoro, chloro, methyl and trifluoromethyl.In another embodiment of the present invention, each R⁰ is independentlyselected from the group consisting of fluoro, chloro andtrifluoromethyl. In another embodiment of the present invention, each R⁰is independently selected from the group consisting of chloro andtrifluoromethyl.

In another embodiment of the present invention, each R⁰ is independentlyselected from the group consisting of fluoro, chloro and methyl. Inanother embodiment of the present invention, each R⁰ is independentlyselected from the group consisting of fluoro and methyl.

In an embodiment of the present invention, the R⁰ group is bound at the4-, 5- and/or 6-position of the benzimidazole core. In anotherembodiment of the present invention, the R⁰ group is bound at the 5-and/or 6-position of the benzimidazole core.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, halogen, lower alkyl, fluorinated lower alkyl,lower alkoxy and fluorinated lower alkoxy. In another embodiment of thepresent invention, R² is selected from the group consisting of hydrogen,halogen, lower alkyl and fluorinated lower alkyl. In another embodimentof the present invention, R² is hydrogen.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of alkyl, hydroxy substituted lower alkyl, fluorinated loweralkyl, monocyclic cycloalkyl-(lower alkyl)- and phenyl-(lower alkyl)-.In another embodiment of the present invention, R¹ is selected from thegroup consisting of lower alkyl, fluorinated lower alkyl and monocycliccycloalkyl-(lower alkyl)-. In an embodiment of the present invention, R¹is selected from the group consisting of alkyl, hydroxy substitutedlower alkyl, fluorinated lower alkyl, cycloalkyl-(lower alkyl)- andphenyl-(lower alkyl)-.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of methyl, ethyl, isopropyl, isobutyl,1-(2,2,2-trifluoroethyl) and cyclopropyl-methyl-, In another embodimentof the present invention, R¹ is selected from the group consisting ofmethyl, ethyl, isopropyl, 1-(2,2,2,-trifluoroethyl) andcyclopropyl-methyl-. In another embodiment of the present invention, R¹is selected from the group consisting of methyl, ethyl, isopropyl and1-(2,2,2-trifluoro-ethyl).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of methyl, ethyl, isopropyl, isobutyl,1-(2-hydroxy-ethyl), 1-(2,2,2-trifluoroethyl), benzyl andcyclopropyl-methyl-. In another embodiment of the present invention, R¹is selected from the group consisting of methyl, ethyl and isopropyl. Inanother embodiment of the present invention, R¹ is selected from thegroup consisting of methyl and ethyl. In another embodiment of thepresent invention, R¹ is methyl.

In an embodiment of the present invention, alternatively R² and R¹ aretaken together as

In another embodiment of the present invention, alternatively R² and R¹are taken together as

In another embodiment of the present invention, alternatively R² and R¹are taken together as

In an embodiment of the present invention, R³ is selected from the groupconsisting of lower alkyl, monocyclic cycloalkyl, phenyl, monocyclicheteroaryl, monocyclic heterocycloalkyl, monocyclic cycloalkyl-(loweralkyl)-, phenyl-(lower alkyl)-, monocyclic heteroaryl-(lower alkyl)- andmonocyclic heterocycloalkyl-(lower alkyl)-; wherein the monocycliccycloalkyl, phenyl, monocyclic heteroaryl or monocyclicheterocycloalkyl, whether alone or as part of a substituent group, isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, lower alkyl, fluorinatedlower alkyl, lower alkoxy, fluorinated lower alkoxy, —C(O)OH,—C(O)O-(lower alkyl) and —C(O)—NR^(A)R^(B); wherein R^(A) and R^(B) areeach independently selected from the group consisting of hydrogen andlower alkyl. In another embodiment of the present invention, R³ isselected from the group consisting of lower alkyl, monocycliccycloalkyl, phenyl, monocyclic cycloalkyl-(lower alkyl)- andphenyl-(lower alkyl)-; wherein the monocyclic cycloalkyl or phenyl,whether alone or as part of a substituent group, is optionallysubstituted with one or to two substituents independently selected fromthe group consisting of halogen, lower alkyl, fluorinated lower alkyl,lower alkoxy and fluorinated lower alkoxy. In another embodiment of thepresent invention, R³ is phenyl; wherein the phenyl is optionallysubstituted with a substituent selected from the group consisting ofhalogen and fluorinated lower alkyl. In another embodiment of thepresent invention, R³ is selected from the group consisting of phenyl,4-fluorophenyl, 4-chlorophenyl and 4-trifluoromethylphenyl. In anotherembodiment of the present invention, R³ is phenyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of lower alkyl and phenyl; wherein the phenyl isoptionally substituted with a substituent selected from the groupconsisting of halogen, lower alkyl and fluorinated lower alkyl. Inanother embodiment of the present invention, R³ is selected from thegroup consisting of methyl, phenyl, 3-chlorophenyl, 4-chlorophenyl,4-fluorophenyl, 4-methylphenyl and 4-trifluoromethylphenyl. In anotherembodiment of the present invention, R³ is selected from the groupconsisting of methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl and4-methylphenyl. In another embodiment of the present invention, R³ isselected from the group consisting of methyl, phenyl, 4-fluorophenyl and4-chlorophenyl. In another embodiment of the present invention, R³ isphenyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of lower alkyl, monocyclic cycloalkyl, phenyl, monocyclicheteroaryl, monocyclic heterocycloalkyl, monocyclic cycloalkyl-(loweralkyl)-, phenyl-(lower alkyl)-, monocyclic heteroaryl-(lower alkyl)- andmonocyclic heterocycloalkyl-(lower alkyl)-; wherein the monocycliccycloalkyl, phenyl, monocyclic heteroaryl or monocyclicheterocycloalkyl, whether alone or as part of a substituent group, isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, lower alkyl, fluorinatedlower alkyl, lower alkoxy, fluorinated lower alkoxy and —S—CF₃. Inanother embodiment of the present invention, R⁴ is selected from thegroup consisting of lower alkyl, monocyclic cycloalkyl, phenyl,monocyclic cycloalkyl-(lower alkyl)- and phenyl-(lower alkyl)-; whereinthe monocyclic cycloalkyl or phenyl, whether alone or as part of asubstituent group, is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, lower alkyl, fluorinated lower alkyl, lower alkoxy, fluorinatedlower alkoxy and —S—CF₃. In another embodiment of the present invention,R⁴ is phenyl-(lower alkyl); wherein the phenyl portion of thephenyl-lower alkyl)- group is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, fluorinated lower alkyl, fluorinated lower alkoxy and —S—CF₃.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of lower alkyl and phenyl-(lower alkyl); wherein thephenyl portion of the phenyl-(lower alkyl)- group is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, fluorinated lower alkyl, fluorinated loweralkoxy and —S—CF₃. In another embodiment of the present invention, R⁴ isselected from the group consisting of benzyl, 4-fluoro-benzyl,3,4-difluoro-benzyl, 3-chloro-4-fluoro-benzyl, 4-difluoromethyl-benzyl,3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-fluoro-4-trifluoromethyl-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,2-fluoro-5-trifluoromethyl-benzyl and 4-trifluoromethyl-thio-benzyl. Inanother embodiment of the present invention, R⁴ is selected from thegroup consisting of 3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-fluoro-4-trifluoromethyl-benzyl and2-fluoro-5-trifluoromethyl-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of4-trifluoromethyl-benzyl, 4-trifluoromethoxy-benzyl and3-fluoro-4-trifluoromethyl-benzyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of methyl, n-butyl, benzyl, 4-chlorophenyl,4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-chloro-4-fluoro-benzyl,3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 3-fluoro-4-trifluoromethyl-benzyl,2-fluoro-5-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl and4-trifluoromethyl-thio-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of n-butyl, benzyl,4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,3-fluoro-4-trifluoromethyl-benzyl, 2-fluoro-5-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of benzyl,4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,3-fluoro-4-trifluoromethyl-benzyl, 2-fluoro-5-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of 4-fluoro-benzyl,3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,4-difluoromethoxy-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-chloro-4-fluoro-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 3-fluoro-4-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl.

In an embodiment of the present invention, R⁴ is other than methyl. Inanother embodiment of the present invention, R⁴ is other than loweralkyl.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. a, R⁰, R¹, R², R³ and R⁴) are independently selected to beany individual substituent or any subset of substituents selected fromthe complete list as defined herein. In another embodiment of thepresent invention is any single compound or subset of compounds selectedfrom the representative compounds listed in Tables 1-2, below.Representative compounds of the present invention are as listed inTables 1-2, below.

TABLE 1 Representative Compounds of Formula (I)

ID No (R⁰)_(a) R¹ R³ R⁴ 1 a = 0 methyl phenyl 3-trifluoromethyl-4-fluoro-benzyl 2 a-0 methyl phenyl 4-trifluoromethoxy- benzyl 3 a = 0methyl phenyl benzyl 4 a = 0 methyl phenyl 3-trifluoromethyl-benzyl 5 a= 0 methyl phenyl 3-trifluoromethoxy- benzyl 6 a = 0 methyl phenyl4-trifluoromethyl-benzyl 7 a = 0 methyl phenyl 3,4-difluoro-benzyl 8 a =0 methyl phenyl 4-fluoro-benzyl 9 a = 0 methyl phenyl 2-fluoro-5-trifluoromethyl-benzyl 10 a = 0 methyl phenyl 3-fluoro-4-trifluoromethyl-benzyl 11 a = 0 methyl phenyl 3-chloro-4-fluoro-benzyl12 a = 0 methyl phenyl 4-trifluoromethyl-thio- benzyl 13 a = 0 methylphenyl 4-difluoromethoxy- benzyl 14 a = 0 ethyl phenyl4-trifluoromethoxy- benzyl 15 a = 0 ethyl phenyl4-trifluoromethyl-benzyl 16 a = 0 methyl 4-fluoro-4-trifluoromethyl-benzyl phenyl 17 a = 0 methyl 4-fluoro-4-trifluoromethoxy- phenyl benzyl 18 a = 0 methyl 4-trifluoro-4-trifluoromethoxy- methyl- benzyl phenyl 19 a = 0 methyl 4-chloro-4-trifluoromethyl-benzyl phenyl 20 a = 0 methyl 4-chloro-4-trifluoromethoxy- phenyl benzyl 21 a = 0 methyl 4-trifluoro-4-trifluoromethyl-benzyl methyl- phenyl 22 a = 0 methyl 4-chloro-3-fluoro-4- phenyl trifluoromethyl-benzyl 23 a = 0 methyl 4-trifluoro-3-fluoro-4- methyl- trifluoromethyl-benzyl phenyl 24 a = 0 methyl4-fluoro- 3-fluoro-4- phenyl trifluoromethyl-benzyl 25 a = 0 ethylphenyl 3-fluoro-4- trifluoromethyl-benzyl 26 a = 0 isobutyl phenyl3-fluoro-4- trifluoromethyl-benzyl 27 a = 0 isobutyl phenyl4-trifluoromethyl-benzyl 28 a = 0 isobutyl phenyl 4-trifluoromethoxy-benzyl 29 5-trifluoro- methyl phenyl 4-trifluoromethyl-benzyl methyl 305-trifluoro- methyl phenyl 4-trifluoromethoxy- methyl benzyl 315-trifluoro- methyl phenyl 3-fluoro-4- methyl trifluoromethyl-benzyl 335-fluoro ethyl phenyl 3-fluoro-4- trifluoromethyl-benzyl 34 5-trifluoro-isopropyl phenyl 4-trifluoromethoxy- methyl benzyl 35 5-trifluoro-isopropyl phenyl 3-fluoro-4- methyl trifluoromethyl-benzyl 36 5-fluoroethyl phenyl 4-trifluoromethoxy- benzyl 37 5-trifluoro- ethyl phenyl3-fluoro-4- methyl trifluoromethyl-benzyl 38 5-fluoro methyl phenyl4-trifluoromethyl-benzyl 39 5-fluoro ethyl phenyl4-trifluoromethyl-benzyl 40 a = 0 1-(2,2,2- phenyl4-trifluoromethyl-benzyl trifluoro - ethyl) 41 5-fluoro methyl phenyl3-fluoro-4- trifluoromethyl-benzyl 42 5-chloro isopropyl phenyl3-fluoro-4- trifluoromethyl-benzyl 43 a = 0 1-(2,2,2- phenyl 3-fluoro-4-trifluoro- trifluoromethyl-benzyl ethyl) 44 a = 0 1-(2,2,2- phenyl4-trifluoromethoxy- trifluoro benzyl -ethyl) 45 5-chloro isopropylphenyl 4-trifluoromethoxy- benzyl 46 5-fluoro methyl phenyl4-trifluoromethoxy- benzyl 48 a = 0 cyclopropyl- phenyl4-trifluoromethoxy- methyl- benzyl 49 a = 0 cyclopropyl- phenyl4-trifluoromethyl-benzyl methyl- 50 a = 0 cyclopropyl- phenyl3-fluoro-4- methyl- trifluoromethyl-benzyl 54 6-methyl methyl phenyl4-trifluoromethoxy- benzyl 55 6-methyl methyl phenyl 3-fluoro-4-trifluoromethyl-benzyl 56 6-methyl methyl phenyl4-trifluoromethyl-benzyl 57 6-trifluoro- methyl phenyl 3-fluoro-4-methyl trifluoromethyl-benzyl 58 6-trifluoro- methyl phenyl4-trifluoromethoxy- methyl benzyl 59 6-trifluoro- methyl phenyl4-trifluoromethyl-benzyl methyl 60 5,6-dimethyl methyl phenyl4-trifluoromethoxy- benzyl 61 5,6-dimethyl methyl phenyl 3-fluoro-4-trifluoromethyl-benzyl 62 4-methyl methyl phenyl 3-fluoro-4-trifluoromethyl-benzyl

TABLE 2 Representative Compounds of Formula (I)

ID No —R² + R¹— R³ R² 51

phenyl 3-fluoro-4-trifluoromethyl- benzyl 52

phenyl 4-trifluoromethoxy-benzyl 53

phenyl 4-trifluoromethyl-benzyl 63

phenyl 4-trifluoromethyl-benzyl 64

phenyl 4-trifluoromethoxy-phenyl

In another embodiment, the present invention is directed to a compoundof formula (I) that exhibits a % Inhibition at 0.2 μM of greater than orequal to about 10% (preferably greater than or equal to about 25%, morepreferably greater than or equal to about 80%, more preferably greaterthan or equal to about 80%), also preferred are greater than or equal to20% at 0.5 uM, and further preferred are greater than or equal to 30% at1 uM, as measured according to the procedure described in BiologicalExample 1, which follows herein. In an embodiment, the present inventionis directed to a compound of formula (I) which exhibits an IC₅₀ of lessthan or 0.100 μM, preferably less than or equal to about 0.050 μM, morepreferably less than or equal to about 0.025 μM, more preferably lessthan or equal to about 0.010 μM, more preferably less than or equal toabout 0.005 μM, as measured according to the procedure described inBiological Example 1, which follows herein.

As used herein, unless otherwise noted, the term “halogen” refers tochlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, include straight and branchedchains having 1 to 8 carbon atoms. Therefore, designated numbers ofcarbon atoms (e.g. C₁₋₈) refer independently to the number of carbonatoms in an alkyl moiety or to the alkyl portion of a largeralkyl-containing substituent. In substituent groups with multiple alkylgroups such as (C₁₋₆alkyl)₂-amino- the C₁₋₆alkyl groups of thedialkylamino may be the same or different. For example, alkyl radicalsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,t-butyl, pentyl and the like. Unless otherwise noted, the term “lower”when used with alkyl means a carbon chain having 1-4 carbon atoms.

As used herein, unless otherwise noted, the term “halogenated loweralkyl” refers to any lower alkyl group as defined above substituted withat least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include, but are not limited to, —CF₃,—CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, and the like. Similarly, unless otherwisenoted, the term “fluorinated lower alkyl” refers to any lower alkylgroup as defined above substituted with at least one fluoro atom.Suitable examples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “hydroxy substitutedalkyl” refers to an alkyl group as defined above substituted with atleast one hydroxy group. Preferably, the alkyl group is substituted withone hydroxy group. Preferably, the hydroxy group is not bound at acarbon atom that is alpha to a nitrogen atom. More preferably, the alkylgroup is substituted with a hydroxy group at the terminal carbon.Suitable examples include, but are not limited to, —CH₂—OH, —CH₂—CH₂—OH,—CH₂—CH(OH)—CH₃, and the like.

As used herein, unless otherwise noted, “alkoxy” refers to an oxygenether radical of the above described straight or branched chain alkylgroups containing 1-8 carbon atoms. For example, methoxy, ethoxy,n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy, n-octyloxy and the like.

As used herein, unless otherwise noted, the term “halogenated loweralkoxy” refers to any lower alkoxy group as defined above substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include, but are not limited to, —OCF₃,—OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like. Similarly, unless otherwisenoted, the term “fluorinated lower alkoxy” refers to any lower alkylgroup as defined above substituted with at least one fluoro atom.Suitable examples include but are not limited to —OCF₃, —OCH₂—CF₃,—OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “aryl” refers to anunsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbonmembers. Examples of aryl rings include phenyl and naphthyl.

As used herein, unless otherwise noted, the term “cycloalkyl” refers tosaturated or partially saturated, monocyclic, polycyclic, or bridgedhydrocarbon rings of 3 to 14 carbon atoms. Examples of such ringsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,1,2,3,4-tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,and adamantyl.

As used herein, unless otherwise noted, “heteroaryl” refers to anaromatic monocyclic or bicyclic aromatic ring structure having 5 to 10ring members and which contains carbon atoms and from 1 to 4 heteroatomsindependently selected from the group consisting of N, O, and S.Included within the term heteroaryl are aromatic rings of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen, andsulfur. In the case of 5 membered rings, the heteroaryl ring preferablycontains one member of nitrogen, oxygen or sulfur and, in addition, upto three additional nitrogens. In the case of 6 membered rings, theheteroaryl ring preferably contains from one to three nitrogen atoms.For the case wherein the 6 membered ring has three nitrogens, at mosttwo nitrogen atoms are adjacent. Examples of heteroaryl groups includefuryl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Unless otherwisenoted, the heteroaryl is attached to its pendant group at any heteroatomor carbon atom that results in a stable structure.

As used herein, unless otherwise noted, the term “heterocycloalkyl”refers to any five to seven membered monocyclic, saturated or partiallyunsaturated ring structure containing at least one heteroatom selectedfrom the group consisting of O, N and S, optionally containing one tothree additional heteroatoms independently selected from the groupconsisting of O, N and S; or a nine to ten membered saturated, partiallyunsaturated or partially aromatic bicyclic ring system containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to four additional heteroatoms independentlyselected from the group consisting of O, N and S. The heterocycloalkylgroup may be attached at any heteroatom or carbon atom of the ring suchthat the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

When a particular group is “substituted” (e.g., alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, etc.), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Unless otherwise noted, for compounds of formula (I), the R¹ group shallbe denoted as bound to the 1-position, the R² group shall be denoted asbound at the 7-position, the R⁴ group shall be denoted as bound to the3-position, and the R⁰ group(s) (which are bound to the benzo-fusedportion of the benzimidazole core) shall be denoted as bound to the 3-,4- and/or 5-positions according to the following numbering convention:

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

DMF=N,N-Dimethylformamide

DMSO=Dimethylsulfoxide

EtOAc=Ethyl acetate

HPLC=High Performance Liquid Chromatography

MeOH=Methanol

MTBE=Methyl-t-butyl ether

Pd/C=Palladium on Carbon

TEA=Triethylamine

TFA=Trifluoroacetic Acid

THF=Tetrahydrofuran

TRPM8=Transient Receptor Potential M8 channel

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need thereof (i.e., asubject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical professional to be at risk of developing said disorder, diseaseor condition. For example, the subject may be deemed at risk ofdeveloping a disorder, disease or condition (and therefore in need ofprevention or preventive treatment) as a consequence of the subject'smedical history, including, but not limited to, family history,pre-disposition, co-existing (comorbid) disorders or conditions, genetictesting, and the like.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

For the purposes of the present invention, the term “antagonist” is usedto refer to a compound capable of producing, depending on thecircumstance, a functional antagonism of an ion channel, including butnot limited to competitive antagonists, non-competitive antagonists,desensitizing agonists, and partial agonists.

For purposes of the present invention, the term “TRPM8-modulated” isused to refer to the condition of being affected by the modulation ofthe TRPM8 channel, including but not limited to, the state of beingmediated by the TRPM8 channel.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems. One skilled inthe art will further recognize that wherein two consecutive reaction orprocess steps are run without isolation of the intermediate product(i.e. the product of the first of the two consecutive reaction orprocess steps), then the first and second reaction or process steps maybe run in the same solvent or solvent system; or alternatively may berun in different solvents or solvent systems following solvent exchange,which may be completed according to known methods.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any rangetherein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follows herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, andthe like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, triflate, and thelike.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” refers to a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” refers to a group which may be attached to a oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:

ee=([α−obs]/[α−max])×100.

One embodiment of the present invention is directed to a compositioncomprising the dextrorotatory enantiomer of a compound of formula (I)wherein said composition is substantially free from the levorotatoryisomer of said compound. In the present context, substantially freemeans less than 25%, preferably less than 10%, more preferably less than5%, even more preferably less than 2% and even more preferably less than1% of the levorotatory isomer calculated as

${\% \mspace{14mu} {dextrorotatory}} = {\frac{( {{mass}\mspace{14mu} {dextrorotatory}} )}{( {{mass}\mspace{14mu} {dextrorotatory}} ) + ( {{mass}\mspace{14mu} {levorotatory}} )} \times 100.}$

Another embodiment of the present invention is a composition comprisingthe levorotatory enantiomer of a compound of formula (I) wherein saidcomposition is substantially free from the dextrorotatory isomer of saidcompound. In the present context, substantially free from means lessthan 25%, preferably less than 10%, more preferably less than 5%, evenmore preferably less than 2% and even more preferably less than 1% ofthe dextrorotatory isomer calculated as

${\% \mspace{14mu} {levorotatory}} = {\frac{( {{mass}\mspace{14mu} {levorotatory}} )}{( {{mass}\mspace{14mu} {dextrorotatory}} ) + ( {{mass}\mspace{14mu} {levorotatory}} )} \times 100.}$

Embodiments of the present invention include prodrugs of compounds offormula (I). In general, such prodrugs will be functional derivatives ofthe compounds that are readily convertible in vivo into the requiredcompound. Thus, in the methods of treating or preventing embodiments ofthe present invention, the term “administering” encompasses thetreatment or prevention of the various diseases, conditions, syndromesand disorders described with the compound specifically disclosed or witha compound that may not be specifically disclosed, but which converts tothe specified compound in vivo after administration to a patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases that may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine, tromethamine and zinc hydroxide.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds offormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of formula (I) may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include elixirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of formula (I) can be administered byinhalation (intratracheal or intranasal) or in the form of a suppositoryor pessary, or they may be applied topically in the form of a lotion,solution, cream, ointment or dusting powder. For example, they can beincorporated into a cream comprising, consisting of, and/or consistingessentially of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of betweenabout 1% and about 10% by weight of the cream, into an ointmentcomprising, consisting of, and/or consisting essentially of a white waxor white soft paraffin base together with any stabilizers andpreservatives as may be required. An alternative means of administrationincludes transdermal administration by using a skin or transdermalpatch.

The pharmaceutical compositions of the present invention (as well as thecompounds of the present invention alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of formula (I) as the active ingredient canbe prepared by mixing the compound(s) with a pharmaceutically acceptablecarrier, a pharmaceutically acceptable diluent, and/or apharmaceutically acceptable excipient according to conventionalpharmaceutical compounding techniques. The carrier, excipient, anddiluent may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral, etc.). Thus, for liquidoral preparations, such as suspensions, syrups, elixirs and solutions,suitable carriers, excipients and diluents include water, glycols, oils,alcohols, flavoring agents, preservatives, stabilizers, coloring agentsand the like; for solid oral preparations, such as powders, capsules andtablets, suitable carriers, excipients and diluents include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations also may beoptionally coated with substances, such as, sugars, or beenterically-coated so as to direct the major site of absorption anddisintegration. For parenteral administration, the carrier, excipientand diluent will usually include sterile water; however otheringredients may be added to increase solubility and preservation of thecomposition. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives, such assolubilizers and preservatives.

A therapeutically effective amount of a compound of formula (I) or apharmaceutical composition thereof includes a dose range from about 0.1mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or,more particularly, from about 10 mg to about 500 mg of active ingredientin a regimen of about 1 to 4 times per day for an average (70 kg) human;although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the diseases, syndromes, conditions, and disordersbeing treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 1, about 10, about 50,about 100, about 150, about 200, about 250, and about 500 milligrams ofthe inventive compound as the active ingredient.

Advantageously, a compound of formula (I) may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily.

Optimal dosages of a compound of formula (I) to be administered may bereadily determined and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease, syndrome, condition, or disorder. Inaddition, factors associated with the particular subject being treated,including subject age, weight, diet and time of administration, willresult in the need to adjust the dose to achieve an appropriatetherapeutic level. The above dosages are thus exemplary of the averagecase. There can be, of course, individual instances wherein higher orlower dosage ranges are merited, and such are within the scope of thisinvention.

Compounds of formula (I) may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of a compound offormula (I) is required for a subject in need thereof.

As antagonists of the TRPM8 channel, the compounds of formula (I) areuseful in methods for treating and preventing a disease, a syndrome, acondition, or a disorder in a subject, including an animal, a mammal anda human in which the disease, the syndrome, the condition, or thedisorder is affected by the modulation of TRPM8 channels. Such methodscomprise, consist of, and consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment or prevention a therapeutically effective amount of acompound, salt, or solvate of formula (I). In particular, the compoundsof formula (I) are useful for preventing or treating pain, or diseases,syndromes, conditions, or disorders causing such pain, or pulmonary orvascular dysfunction. More particularly, the compounds of formula (I)are useful for preventing or treating inflammatory pain, inflammatoryhypersensitivity conditions, neuropathic pain, anxiety, depression, andcardiovascular disease aggravated by cold, including peripheral vasculardisease, vascular hypertension, pulmonary hypertension, Raynaud'sdisease, and coronary artery disease, by administering to a subject inneed thereof a therapeutically effective amount of a compound of formula(I).

Examples of inflammatory pain include pain due to a disease, condition,syndrome, disorder, or a pain state including inflammatory boweldisease, visceral pain, migraine, post operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor, musculoskeletal diseases, skin diseases,toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic bladder, interstitial cystitis,urinary tract infection, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis, sinus headache, tension headache, orarachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia, which can befurther distinguished as inflammatory somatic hyperalgesia orinflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesiacan be characterized by the presence of an inflammatory hyperalgesicstate in which a hypersensitivity to thermal, mechanical and/or chemicalstimuli exists. Inflammatory visceral hyperalgesia can also becharacterized by the presence of an inflammatory hyperalgesic state, inwhich an enhanced visceral irritability exists.

Examples of inflammatory hyperalgesia include a disease, syndrome,condition, disorder, or pain state including inflammation,osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominalpain, musculoskeletal diseases, skin diseases, post operative pain,headaches, toothache, burn, sunburn, insect sting, neurogenic bladder,urinary incontinence, interstitial cystitis, urinary tract infection,cough, asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis,irritable bowel syndrome, inflammatory bowel diseases including Crohn'sDisease or ulcerative colitis.

One embodiment of the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate offormula (I).

A further embodiment of the present invention is directed to a methodfor treating inflammatory visceral hyperalgesia in which an enhancedvisceral irritability exists, comprising, consisting of, and/orconsisting essentially of the step of administering to a subject in needof such treatment a therapeutically effective amount of a compound, saltor solvate of formula (I).

A further embodiment of the present invention is directed to a methodfor treating neuropathic cold allodynia in which a hypersensitivity to acooling stimuli exists, comprising, consisting of, and/or consistingessentially of the step of administering to a subject in need of suchtreatment a therapeutically effective amount of a compound, salt orsolvate of formula (I).

Examples of a neuropathic pain include pain due to a disease, syndrome,condition, disorder, or pain state including cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumor, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndrome,fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminalneuralgia, glossopharyngeal neuralgia, postherpetic neuralgia andcausalgia), lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, vulvodynia,or vidian neuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, syndrome, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

General Synthetic Methods

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with cyanogenbromide, in an aqueous organic solvent such as methanol, ethanol,isopropanol, and the like, preferably at about room temperature, toyield the corresponding compound of formula (VI).

The compound of formula (VI) is reacted with a suitably substitutedcompound of formula (VII), a known compound or compound prepared byknown methods, in the presence of an organic base such as pyridine, TEA,and the like, neat or in an organic solvent such as THF, methylenechloride, chloroform, and the like, preferably at about from roomtemperature to about 60° C., to yield the corresponding compound offormula (VIII).

The compound of formula (VIII) is reacted with a suitably substitutedcompound of formula (IX), wherein LG¹ is a suitably selected leavinggroup such as Br, Cl, and the like, in the presence of a base,preferably an inorganic base, such as K₂CO₃, Na₂CO₃, pyridine, TEA, andthe like, in an organic solvent such as DMF, methylene chloride,acetonitrile, and the like, to yield a mixture of the correspondingcompound of formula (I) and the corresponding compound of formula (II).

Preferably the compound of formula (I) is separated from the mixture,according to known methods, for example by column chromatography, HPLC,crystallization, and the like.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1N-[1-Methyl-3-(3-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide(Compound #4)

Step A: N-(1-Methyl-1H-benzimidazol-2-yl)-benzenesulfonamide

To a solution of 1-methyl-1H-benzimidazol-2-ylamine (2.65 g, 18.0 mmol)in anhydrous pyridine (15 mL) was added benzenesulfonyl chloride (2.30mL, 18.0 mmol). The resulting mixture was stirred at 60° C. for 1 day.After addition of water, a precipitate was obtained, a mixture ofN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide andN-(1-benzenesulfonyl-3-methyl-1,3-dihydro-benzoimidazol-2-ylidene)-benzenesulfonamide.The mixture was then treated with 1 N NaOH. The insoluble part of themixture was determined to beN-(1-benzenesulfonyl-3-methyl-1,3-dihydro-benzoimidazol-2-ylidene)-benzenesulfonamide.The alkaline solution was acidified with acetic acid and the resultingsolid was collected by filtration, washed with H₂O, hexanes to yieldN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide. MS 288 (M+1)⁺.

Step B:N-[1-Methyl-3-(3-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide

To a solution of N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide(100 mg, 0.35 mmol) in DMF (2 mL) was added1-bromomethyl-3-trifluoromethyl-benzene (166.4 mg, 0.70 mmol) andpotassium carbonate (48 mg). The resulting mixture was heated to 120° C.in a microwave reactor for 1 h and then diluted with EtOAc, washed withH₂O and the organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resultant residue was purified by flashcolumn chromatography (SiO₂), eluting with a hexanes-EtOAc gradient toyieldN-[1-methyl-3-(3-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide(2^(nd) compound to elute off the column, 99.0 mg, 64%). MS 446 (M+1)⁺.

The compounds of the present invention as listed in Table 3 below, weresimilarly prepared according to the procedure as described in Example 1above, substituting suitably selected reagents, starting materials andpurification methods known to those skilled in the art.

TABLE 3 Measured Mass Spec. ID No. MS (M + 1)⁺ 1 464 2 462 5 462 7 414 8396 9 464 10 464 11 430 12 478 14 476 15 460 19 480 25 478 26 506 27 48828 504

Example 2N-[1-Ethyl-5-fluoro-3-(4-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide(Compound #39)

Step A: 1-Ethyl-5-fluoro-1H-benzimidazol-2-ylamine

To a solution of N¹-ethyl-4-fluoro-benzene-1,2-diamine (1.54 g, 10.0mmol) in MeOH (20 mL) and H₂O (20 mL) was added cyanogen bromide (2.1mL, 10.5 mmol, 5.0 M in acetonitrile). The resulting mixture was stirredat room temperature over night. The resulting mixture was then adjustedto pH>9 with coned NH₄OH and the resulting solid was collected byfiltration, washed with H₂O and hexanes to yield1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine MS 180 (M+1)⁺

Step B: N-(1-Ethyl-5-fluoro-1H-benzimidazol-2-yl)-benzenesulfonamide

N-(1-Ethyl-5-fluoro-1H-benzoimidazol-2-yl)-benzenesulfonamide wasprepared according to the procedure as described in Example 1, STEP A,substituting 1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine. MS 320 (M+1)⁺.

Step C:N-[1-Ethyl-5-fluoro-3-(4-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide

N-[1-Ethyl-5-fluoro-3-(4-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamidewas prepared according to the procedure as described in Example 1, STEPB, substituting 1-bromomethyl-4-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene, and further substitutingN-(1-ethyl-5-fluoro-1H-benzimidazol-2-yl)-benzenesulfonamide forN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide. MS 478 (M+1)⁺.

The compounds of the present invention as listed in Table 4 below, weresimilarly prepared according to the procedure as described in Example 2above, substituting suitably selected reagents, starting materials andpurification methods known to those skilled in the art.

TABLE 4 Measured Mass Spec. ID No. MS (M + 1)⁺ 29 514 30 530 31 532 33496 34 558 35 560 36 494 37 546 42 526 45 524 51 490 52 488 53 472

Example 3N-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3-(2,2,2-trifluoro-ethyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide(Compound #43)

Step A: (2-Nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine

A mixture of 1-fluoro-2-nitro-benzene (1.55 g, 11.0 mmol),2,2,2-trifluoro-ethylamine (3.27 g, 33.0 mmol) and DMSO (4.5 mL) washeated at 120° C. for 24 h. The resulting mixture was poured ontoice/H₂O and the resultant precipitate was collected by filtration,washed with H₂O and hexanes to yield(2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine MS 221 (M+1)⁺.

Step B: N-(2,2,2-Trifluoro-ethyl)-benzene-1,2-diamine

To a solution of (2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amin (2.16 g,9.8 mmol) in THF (6 mL) and MeOH (24 mL) at 0° C. was added ammoniumformate (2.47 g, 39.2 mmol). The resulting mixture was purged withnitrogen, then 10% Pd/C (57 mg) was added. The ice bath was removed andthe reaction mixture was stirred at room temperature for 5 h. Theresulting mixture was filtered over CELITE®, washing with EtOAc. Removalof the solvent in vacuo yieldN-(2,2,2-trifluoro-ethyl)-benzene-1,2-diamine, which was used in thenext step without further purification. MS 191 (M+1)⁺.

Step C: 1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-ylamine

1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-ylamine was preparedaccording to the procedure as described in Example 2, STEP A above,substituting N-(2,2,2-trifluoro-ethyl)-benzene-1,2-diamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine. MS 216 (M+1)⁺.

Step D:N-[1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamide

N-[1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamidewas prepared according to the procedure as described in Example 1, STEPA, above, substituting1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 356 (M+1)⁺.

Step E:N-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3-(2,2,2-trifluoro-ethyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide

N-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3-(2,2,2-trifluoro-ethyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamidewas prepared according to the procedure as described in Example 1, STEPB, above, substituting 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzenefor 1-bromomethyl-3-trifluoromethyl-benzene and further substitutingN-[1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamidefor N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide. MS 532 (M+1)⁺.

Compound #44 (MS 530 (M+1)⁺) was similarly prepared according to theprocedure as described above in Example 3, substituting suitablyselected reagents, starting materials and purification methods known tothose skilled in the art.

Example 4N-[1-Cyclopropylmethyl-3-(3-fluoro-4-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide(Compound #50)

Step A: N-Cyclopropylmethyl-benzene-1,2-diamine

To a solution of benzene-1,2-diamine (1.62 g, 15.0 mmol) andcyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in MeOH (15 mL) at 0° C.was added NaCNBH₃ (2.07 g, 33.0 mmol) and acetic acid (0.2 mL). The icebath was removed and the resulting mixture was stirred at roomtemperature over night. The resulting mixture was diluted with EtOAc,washed with H₂O, dried over Na₂SO₄, filtered, and concentrated in vacuo.The resultant residue was purified by flash column chromatography(SiO₂), eluting with a hexanes-EtOAc gradient to yieldN-cyclopropylmethyl-benzene-1,2-diamine (836 mg, 34%). MS 163 (M+1)⁺.

Step B: 1-Cyclopropylmethyl-1H-benzimidazol-2-ylamine

1-Cyclopropylmethyl-1H-benzimidazol-2-ylamine was prepared according tothe procedure as described in Example 2, STEP A, substitutingN-cyclopropylmethyl-benzene-1,2-diamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine MS 188 (M+1)⁺.

Step C: N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-benzenesulfonamide

N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-benzenesulfonamide wasprepared according to the procedure as described in Example 1, STEP A,substituting 1-cyclopropylmethyl-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 328 (M+1)⁺.

Step D:N-[1-Cyclopropylmethyl-3-(3-fluoro-4-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide

N-[1-Cyclopropylmethyl-3-(3-fluoro-4-trifluoromethyl-benzyl)-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamidewas prepared according to the procedure as described in Example 1, STEPB, substituting 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene and further substitutingN-(1-cyclopropylmethyl-1H-benzimidazol-2-yl)-benzenesulfonamide forN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide. MS 504 (M+1)⁺.

Compounds #48 (MS 502 (M+1)⁺) and #49 (MS 486 (M+1)⁺) were similarlyprepared according to the procedure as described above in Example 4,substituting suitably selected reagents, starting materials andpurification methods known to those skilled in the art.

Example 5N-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3,5-dimethyl-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide (Compound #55)

Step A: Methyl-(5-methyl-2-nitro-phenyl)-amine

To a solution of 5-methyl-2-nitro-phenylamine (3.04 g, 20.0 mmol) inanhydrous DMF (20 mL) at 0° C. was portionwise added 95% NaH (528 mg,22.0 mmol) and the resulting mixture stirred for 10 min. A solution ofiodomethane (1.25 mL, 20.0 mmol) in anhydrous DMF (10 mL) was thenadded. The ice bath was removed and the resulting mixture was stirred atroom temperature overnight. The resulting mixture was diluted withwater, the solid was collected by filtration, washed with H₂O andhexanes to yield methyl-(5-methyl-2-nitro-phenyl)-amine MS 167 (M+1)⁺.

Step B: 4,N²-Dimethyl-benzene-1,2-diamine

To a solution of methyl-(5-methyl-2-nitro-phenyl)-amine (2.47 g, 14.9mmol), ammonium formate (15 g, 237.9 mmol) in THF (7 mL) and MeOH (35mL) at room temperature was added 10% Pd/C (650 mg) and the resultingmixture was stirred at room temperature for 10 min. The resultingmixture was then filtered over CELITE® and concentrated in vacuo. Theresulting residue was diluted with CH₂Cl₂, washed with H₂O and theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The resultant residue was purified by flash column chromatography(SiO₂), eluting with a hexanes-EtOAc gradient to yield4,N²-dimethyl-benzene-1,2-diamine

Step C: 1,6-Dimethyl-1H-benzimidazol-2-ylamine

1,6-Dimethyl-1H-benzimidazol-2-ylamine was prepared according to theprocedure as described in Example 2, STEP A, substituting4,N²-dimethyl-benzene-1,2-diamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine. MS 162 (M+1)⁺.

Step D: N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-benzenesulfonamide

N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-benzenesulfonamide was preparedaccording to the procedure as described in Example 1, STEP A,substituting 1,6-dimethyl-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine. MS 302 (M+1)⁺.

Step E:N-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3,5-dimethyl-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamide

N-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3,5-dimethyl-1,3-dihydro-benzimidazol-2-ylidene]-benzenesulfonamidewas prepared according to the procedure as described in Example 1, STEPB, substituting 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene and further substitutingN-(1,6-dimethyl-1H-benzimidazol-2-yl)-benzenesulfonamide forN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide. MS 478 (M+1)⁺.

The compounds of the present invention as listed in Table 5 below, weresimilarly prepared according to the procedure as described in Example 5above, substituting suitably selected reagents, starting materials andpurification methods known to those skilled in the art.

TABLE 5 Measured Mass Spec. ID No. MS (M + 1)⁺ 57 532 58 530 59 514 61492 62 478

Example 6N-[1-(4-Trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamideTFA salt (Compound #63)

Step A: 3,4-Dihydro-2H-benzo[1,4]oxazin-5-ylamine

3,4-Dihydro-2H-benzo[1,4]oxazin-5-ylamine was prepared according to theprocedure as described in Example 5, STEP B, substituting5-nitro-3,4-dihydro-2H-benzo[1,4]oxazine for4,N²-dimethyl-benzene-1,2-diamine MS 151 (M+1)⁺.

Step B: 3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-ylamine

3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-ylamine was preparedaccording to the procedure as described in Example 2, STEP A,substituting 3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine MS 176 (M+1)⁺.

Step C:N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide

N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamidewas prepared according to the procedure as described in Example 1, STEPA, substituting 3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 316 (M+1)⁺.

Step D:N-[1-(4-Trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamidetrifluoroacetic acid salt

To a solution ofN-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide(125 mg, 0.40 mmol) in DMF (2.5 mL) was added1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) andpotassium carbonate (55 mg). The resulting mixture was heated to 120° C.in a microwave reactor for 1 h and then diluted with EtOAc, washed withH₂O and the organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resultant residue was purified by flashcolumn chromatography (SiO₂), eluting with a hexanes-EtOAc gradient toyieldN-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide(2^(nd) compound to elute off the column); which was further purified byHPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing0.05% trifluoroacetic acid) to yieldN-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamidetrifluoroacetic acid salt. MS 474 (M+1)⁺.

Compound #64 (MS 490 (M+1)⁺) was similarly prepared according to theprocedure as described above in Example 6, substituting suitablyselected reagents, starting materials and purification methods known tothose skilled in the art.

Biological Example 1 In Vitro Canine TRPM8 Functional Assay

The functional activity of representative compounds of the formula (I)of the present invention was quantified by measuring changes inintracellular calcium concentration using a Ca²⁺-sensitive fluorescentdye. The changes in fluorescent signal were monitored by a fluorescenceplate reader, either a FLIPR™ (Molecular Devices) or FDSS (Hamamatsu).Increases in intracellular Ca²⁺ concentration were readily detected uponactivation with icilin.

HEK293 cells stably expressing canine TRPM8 were routinely grown asmonolayers in Dulbecco's minimum essential medium supplemented with 10%FBS, 2 mM L-glutamine, 100 units/mL penicillin, 100 ug/mL streptomycinand 400 μg/mL G418. Cells were maintained in 5% CO₂ at 37° C. At 24 hrprior to assay, cells were seeded in black wall, clear-basepoly-D-lysine coated 384-well plates (BD Biosciences, NJ, USA) at adensity of 5,000 cells per well in culture medium and grown overnight in5% CO₂ at 37° C. On assay day, growth media was removed, and cells wereloaded with Calcium 3 Dye (Molecular Devices) for 35 min at 37° C.,under 5% CO₂ and then incubated for 25 min at room temperature andatmosphere. Subsequently, cells were tested for agonist-inducedincreases in intracellular Ca²⁺ levels using FLIPR™ or FDSS. Cells weretreated with compounds of the formula (I) at varying concentrations andintracellular Ca²⁺ was measured for 5 min prior to the addition oficilin to all wells to achieve a final concentration that producesapproximately an 80% maximal response. EC₅₀ or IC₅₀ values for compoundsof the present invention were determined from eight-pointconcentration-response studies and represent the concentration ofcompound required to elicit or inhibit 50% of the maximal response,respectively.

Maximal fluorescence intensity (FI) achieved upon addition of icilin wasexported from the FLIPR or FDSS software and further analyzed usingGraphPad Prism 3.02 (Graph Pad Software Inc., CA, U.S.A.). Basal FI wassubtracted prior to normalizing data to percent of maximal response.Curves were generated using the average of quadruplicate wells for eachdata point using nonlinear regression of either sigmoidal dose responseor sigmoidal dose response (variable slope). Finally, the EC₅₀ and IC₅₀values were calculated with the best-fit curve determined by GraphPadPrism

Representative compounds of the present invention were tested accordingto the procedures as described in Biological Example 1 above, withresults as listed in Table 6, below.

TABLE 6 Biological Activity Measurements ID No IC₅₀(μM) % Inh @ 0.2 μM 140 2 34 3 8 4 42 5 50 6 2 7 24 8 20 9 39 10 22 11 38 12 11 13 9 14 0.10075 15 0.069 85 16 1 17 6 18 1 19 13 20 2 21 8 22 6 23 3 24 3 25 62 260.014 100 27 0.043 71 28 0.058 70 29 19 30 17 31 0.039 71 33 70 34 0.02495 35 0.010 100 36 36 37 0.005 93 38 1 39 26 40 9 41 6 42 0.026 95 430.021 89 44 37 45 66 46 1 48 67 49 0.110 71 50 0.086 94 51 14 52 18 5316 54 6 55 18 56 1 57 45 58 25 59 20 60 5 61 14 62 19 63 34 64 61

Representative compounds of the present invention as listed in Table 7,below were re-tested according to the procedure as described above. Testsamples were prepared by diluting a 10 mM stock solution of testcompound with 100% DMSO prior to addition to assay buffer.

TABLE 7 Biological Activity Measurements ID No IC₅₀(μM) % Inh @ 1 μM 340 6 65 13 0.764 55 16 57 17 0.606 60 18 0.635 57 20 0.430 74 21 0.58859 22 0.512 77 23 0.764 59 24 0.379 85 38 24 40 0.426 57 41 79 46 58 540.645 55 56 40 60 48

Biological Example 2

Icilin was initially developed as a “super-cooling” compound by DelmarChemicals Ltd. Subsequently it was shown to be one of the most potentknown agonists of TRPM8 (McKemy D D, et al. Nature 2002, 416(6876):52-8), having an EC₅₀=0.2 μM in stimulating calcium ion influx intoTRPM8 transfected cells (Behrendt H J et al. Brit J Pharmacol 2004,141(4): 737-45). Initial in vivo testing of icilin showed it to cause“wet-dog” shakes in rats. Similar shaking or jumping behavior was alsoevident in mice, rabbits, cats, dogs and monkeys. In humans, icilinproduced a sensation of coolness on contact with mucous membranes, coldprickling when 0.1 mg was dropped on the tongue and coldness in themouth, pharynx and chest lasting 30-60 minutes when 5-10 mg was ingestedorally (Wei E T, Seid D A, J Pharm Pharmacol. 1983, 35, 110). Theinhibition or reversal of icilin-induced shaking behaviors in rodentsprovides evidence for the utility of TRPM8 antagonists in treating orpreventing a disease or condition in a mammal in which the disease orcondition is affected by the modulation of TRPM8 receptors.

Inhibition of Icilin-Induced “Wet-Dog” Shakes in Rats

Male Sprague Dawley rats (22-450 g, Charles River Labs, n=6-9/treatment)were used to evaluate the ability of test compounds to blockicilin-induced “wet-dog” shakes (WDS). The test compound wasadministered at 10 mg/kg in an appropriate vehicle, such ashydroxypropyl-β-cyclodextrin (HP-β-CD), methocellulose, 10% Solutol, H₂Oor the like, by the appropriate route (e.g., i.p or p.o), 30-60 minbefore icilin. Icilin was then administered in PEG-400 or 10%solutol/H₂O, at 1.0 or 3.0 mg/kg, i.p. and spontaneous “wet-dog” shakeswere counted 10-20 min post-icilin.

A representative compound of the present invention was tested at 10mg/kg p.o. and 60 min pre-icilin, according to the procedure describedabove. Results, as listed in Table 8 below, are presented as a percentinhibition of shakes, which was calculated as [1−(test compound WDScount/vehicle WDS count)]×100.

TABLE 8 Inhibition of icilin-induced “wet -dog” shakes in rats ID No.Vehicle % Inhibition 37 0.5% HPMC 0.6

Solid Dosage Formulation

As a specific embodiment of an oral composition, 100 mg of Compound #37,prepared as in Example 2, is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size 0 hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1-8. (canceled)
 9. A process for making a pharmaceutical compositioncomprising mixing a compound of formula (I) and a pharmaceuticallyacceptable carrier:

wherein: a is an integer from 0 to 2; each R⁰ is independently selectedfrom the group consisting of halogen, C₁₋₂alkyl and fluorinated C₁₋₂alkyl; R² is hydrogen; R¹ is selected from the group consisting of loweralkyl, fluorinated lower alkyl and monocyclic cycloalkyl-(lower alkyl)-;alternatively R² and R¹ are taken together as

R³ is phenyl; wherein the phenyl is optionally substituted with asubstituent selected from the group consisting of halogen andfluorinated lower alkyl; R⁴ is selected from the group consisting ofbenzyl, 4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-chloro-4-fluoro-benzyl,4-difluoromethyl-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-fluoro-4-trifluoromethyl-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 2-fluoro-5-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl; provided that when a is 0, R¹ is methyl,R² is hydrogen and R⁴ is methyl; then R³ is other than methyl, phenyl or4-methylphenyl; or pharmaceutically acceptable salt thereof. 10-19.(canceled)
 20. A method for treating cardiovascular disease aggravatedby cold, including peripheral vascular disease, vascular hypertension,pulmonary hypertension, Raynaud's disease, and coronary artery disease,comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of formula (I):

wherein: a is an integer from 0 to 2; each R⁰ is independently selectedfrom the group consisting of halogen, C₁₋₂alkyl and fluorinatedC₁₋₂alkyl; R² is hydrogen; R¹ is selected from the group consisting oflower alkyl, fluorinated lower alkyl and monocyclic cycloalkyl-(loweralkyl)-; alternatively R² and R¹ are taken together as

R³ is phenyl; wherein the phenyl is optionally substituted with asubstituent selected from the group consisting of halogen andfluorinated lower alkyl; R⁴ is selected from the group consisting ofbenzyl, 4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-chloro-4-fluoro-benzyl,4-difluoromethyl-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-fluoro-4-trifluoromethyl-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 2-fluoro-5-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl; provided that when a is 0, R¹ is methyl,R² is hydrogen and R⁴ is methyl; then R³ is other than methyl, phenyl or4-methylphenyl; or pharmaceutically acceptable salt thereof. 21.(canceled)